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569 Investigating the Role of FOXA2 During the Transition to Neuroendocrine Prostate Cancer
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- Richard Garner, Nicholas Brady, Kate Dunmore, Richa Singh, Alyssa Bagadion, Andrea Sboner, Olivier Elemento, Brian Robinson, Himisha Beltran, David S. Rickman
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- Journal:
- Journal of Clinical and Translational Science / Volume 8 / Issue s1 / April 2024
- Published online by Cambridge University Press:
- 03 April 2024, pp. 148-149
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OBJECTIVES/GOALS: The goal of this project is to characterize the efficacy of FOXA2 as a potential biomarker for patients with metastatic castrate-resistant prostate adenocarcinoma (CRPC) before transitioning to neuroendocrine prostate cancer (NEPC). NEPC currently has no therapeutic options and poor mechanistic understand of its origins. METHODS/STUDY POPULATION: In our study, we have utilized a multi-omics approach to characterize the potential efficacy of FOXA2 as a prognostic biomarker in numerous patient-derived castrate-resistant prostate cancer (CRPC) models. We have performed ATAC-, ChIP-, RNA-seq and proteomics to fully characterize where FOXA2 is binding genome-wide, how FOXA2 alters chromatin accessibility dynamics, identify regulatory gene targets of FOXA2, and identify FOXA2 protein-protein interactors. We have supported these findings using publicly available data from independent CRPC and NEPC patient cohorts and prostate cancer cell models. RESULTS/ANTICIPATED RESULTS: Our findings show that FOXA2 overexpression suppressed androgen signaling and promoted progression to a NEPC phenotype under short- and long-term androgen deprivation conditions, respectively. Further, FOXA2 redirected the chromatin accessibility landscape to be consistent with an NEPC gene expression program, including increased chromatin accessibility for key NEPC transcription factors. FOXA2 ChIP-seq showed FOXA2 to be bound at known NEPC driver genes and epigenetic modifiers across multiple stages of prostate cancer progression. Lastly, we discovered that FOXA2 physically interacts with key NEPC TFs and epigenetic regulators, suggesting that these FOXA2 physical interactions are required for NEPC progression. DISCUSSION/SIGNIFICANCE: This project will determine the efficacy of FOXA2 as a biomarker in advanced prostatecancer samples, which will translate as a potentially useful tool for clinicians to use for treatment of advanced prostate cancer patients.
Neurobiological sensitivity to unpredictable threat and familial risk for the internalizing and externalizing spectra in adolescents
- Clare C. Beatty, Rachel A. Ferry, Nicholas R. Eaton, Daniel N. Klein, Brady D. Nelson
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- Journal:
- Psychological Medicine / Volume 53 / Issue 12 / September 2023
- Published online by Cambridge University Press:
- 19 August 2022, pp. 5395-5404
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Background
Adolescence is a key developmental period for the emergence of psychiatric disorders. However, there is still no consensus on the core mechanisms of dysfunction in youth. Neurobiological sensitivity to unpredictable threat has been associated with several psychiatric disorders in adults. The present study examined adolescent defensive motivation (startle reflex) and attention (event-related potentials) in anticipation of unpredictable threat in relation to both adolescent and maternal (i.e. familial risk) internalizing and externalizing spectra.
MethodsThe sample included 395 15-year-old adolescents and their biological mothers. Adolescent startle potentiation and probe P300 suppression (indicating increased attention to threat) were measured in anticipation of predictable and unpredictable threat. Adolescent and maternal lifetime history of psychiatric disorders were assessed via semi-structured diagnostic interviews, and confirmatory factor analysis was used to model internalizing and externalizing spectra.
ResultsThe adolescent internalizing spectrum was positively associated with adolescent startle potentiation and probe P300 suppression to unpredictable threat. Conversely, the adolescent externalizing spectrum was negatively associated with adolescent P300 suppression to unpredictable threat. The maternal internalizing spectrum was positively associated with adolescent startle potentiation to unpredictable threat and P300 suppression to both predictable and unpredictable threat. The maternal externalizing spectrum was negatively associated with adolescent startle potentiation to unpredictable threat and P300 suppression to both predictable and unpredictable threat. Adolescent and maternal internalizing and externalizing spectra were independently related to adolescent startle potentiation and P300 suppression.
ConclusionsAdolescent neurobiological sensitivity to unpredictable threat is associated with both personal history and familial risk for the internalizing and externalizing spectra.
The Hierarchical Taxonomy of Psychopathology (HiTOP) in psychiatric practice and research
- Roman Kotov, David C. Cicero, Christopher C. Conway, Colin G. DeYoung, Alexandre Dombrovski, Nicholas R. Eaton, Michael B. First, Miriam K. Forbes, Steven E. Hyman, Katherine G. Jonas, Robert F. Krueger, Robert D. Latzman, James J. Li, Brady D. Nelson, Darrel A. Regier, Craig Rodriguez-Seijas, Camilo J. Ruggero, Leonard J. Simms, Andrew E. Skodol, Irwin D. Waldman, Monika A. Waszczuk, David Watson, Thomas A. Widiger, Sylia Wilson, Aidan G. C. Wright
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- Journal:
- Psychological Medicine / Volume 52 / Issue 9 / July 2022
- Published online by Cambridge University Press:
- 02 June 2022, pp. 1666-1678
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The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.
Contrasting effects of high-starch and high-sugar diets on ruminal function in cattle
- Andrea Francesio, Lorenzo Viora, Matt J. Denwood, Will Tulley, Nicola Brady, Peter Hastie, Andrew Hamilton, Christopher Davison, Craig Michie, Nicholas N. Jonsson
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- Journal:
- Journal of Dairy Research / Volume 87 / Issue 2 / May 2020
- Published online by Cambridge University Press:
- 21 April 2020, pp. 175-183
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- May 2020
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The experiment reported in this research paper aimed to determine whether clinical and subclinical effects on cattle were similar if provided with isoenergetic and isonitrogenous challenge diets in which carbohydrate sources were predominantly starch or sugar. The study was a 3 × 3 Latin square using six adult Jersey cows with rumen cannulae, over 9 weeks. In the first 2 weeks of each 3 week experimental period cows were fed with a maintenance diet and, in the last week, each animal was assigned to one of three diets: a control diet (CON), being a continuation of the maintenance diet; a high starch (HSt) or a high sugar (HSu) diet. Reticuloruminal pH and motility were recorded throughout the study period. Blood and ruminal samples were taken on day-1 (TP-1), day-2 (TP-2) and day-7 (TP-7) of each challenge week. Four clinical variables were recorded daily: diarrhoea, inappetence, depression and ruminal tympany. The effects of treatment, hour of day and day after treatment on clinical parameters were analysed using linear mixed effects (LME) models. Although both challenge diets resulted in a decline in pH, an increase in the absolute pH residuals and an increase in the number of minutes per day under pH 5.8, systemic inflammation was only detected with the HSt diet. The challenge diets differentially modified amplitude and period of reticuloruminal contractions compared with CON diet and both were associated with an increased probability of diarrhoea. The HSu diet reduced the probability of an animal consuming its complete allocation. Because the challenge diets were derived from complex natural materials (barley and molasses respectively), it is not possible to assign all the differential effects to the difference in starch and sugar concentration: non-starch components of barley or non-sugar components of molasses might have contributed to some of the observations. In conclusion, substituting much of the starch with sugar caused no substantial reduction in the acidosis load, but inflammatory response was reduced while feed rejection was increased.
Epidemiology of Ventilator-Associated Pneumonia in a Long-Term Acute Care Hospital
- Allan J. Walkey, Christine Campbell Reardon, Carol A. Sulis, R. Nicholas Nace, Martin Joyce-Brady
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- Journal:
- Infection Control & Hospital Epidemiology / Volume 30 / Issue 4 / April 2009
- Published online by Cambridge University Press:
- 02 January 2015, pp. 319-324
- Print publication:
- April 2009
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Objective.
To characterize the epidemiology and microbiology of ventilator-associated pneumonia (VAP) in a long-term acute care hospital (LTACH).
Design.Retrospective study of prospectively identified cases of VAP.
Setting.Single-center, 207-bed LTACH with the capacity to house 42 patients requiring mechanical ventilation, evaluated from April 1, 2006, through January 31, 2008.
Methods.Data on the occurrence of VAP were collected prospectively as part of routine infection surveillance at Radius Specialty Hospital. After March 2006, Radius Specialty Hospital implemented a bundle of interventions for the prevention of VAP (hereafter referred to as the VAP-bundle approach). A case of VAP was defined as a patient who required mechanical ventilation at Radius Specialty Hospital for at least 48 hours before any symptoms of pneumonia appeared and who met the Centers for Disease Control and Prevention criteria for VAP. Sputum samples were collected from a tracheal aspirate if there was clinical suspicion of VAP, and these samples were semi-quantitatively cultured.
Results.During the 22-month study period, 23 cases of VAP involving 19 patients were associated with 157 LTACH admissions (infection rate, 14.6%), corresponding to a rate of 1.67 cases per 1,000 ventilator-days, which is a 56% reduction from the VAP rate of 3.8 cases per 1,000 ventilator-days reported before the implementation of the VAP-bundle approach (P<.001). Microbiological data were available for 21 (91%) of 23 cases of VAP. Cases of VAP in the LTACH were frequently polymicrobial (mean number ± SD, 1.78 ± 1.0 pathogens per case of VAP), and 20 (95%) of 21 cases of VAP had at least 1 pathogen (Pseudomonas species, Acinetobacter species, gram-negative bacilli resistant to more than 3 antibiotics, or methicillin-resistant Staphylococcus aureus) cultured from a sputum sample. LTACH patients with VAP were more likely to have a neurological reason for ventilator dependence, compared with LTACH patients without VAP (69.6% of cases of VAP vs 39% of cases of respiratory failure; P = .014). In addition, patients with VAP had a longer length of LTACH stay, compared with patients without VAP (median length of stay, 131 days vs 39 days; P = .002). In 6 (26%) of 23 cases of VAP, the patient was eventually weaned from use of mechanical ventilation. Of the 19 patients with VAP, 1 (5%) did not survive the LTACH stay.
Conclusions.The VAP rate in the LTACH is lower than the VAP rate reported in acute care hospitals. Cases of VAP in the LTACH were frequently polymicrobial and were associated with multidrug-resistant pathogens and increased length of stay. The guidelines from the Centers for Disease Control and Prevention that are aimed at reducing cases of VAP appear to be effective if applied in the LTACH setting.